5757
J. Am. Chem. SOC. 1995,117, 5151-5162
Highly Diastereoselective Cyclopentane Construction: Enantioselective Synthesis of the Dendrobatid Alkaloid 25 1F Douglass F. Taber* and Kamfia K. You Contribution f f o m the Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware I9716 Received November 21, 1994@
--
Abstract: We report the first total synthesis, and thus structural confirmation, of the dendrobatid alkaloid 251F (l), based on the retrosynthetic analysis illustrated (1 4). Key observations in this synthesis are that both the Rh-mediated cyclization of 4 and the anionic cyclization of 2 proceed with excellent diastereoselectivity.
In 1992 Daly and Spande reported' the isolation and structural elucidation, primarily by high field 'H and 13CNMR and mass spectrometry, of alkaloid 251F (1) from the skin exudate of the dendrobatid poison frog Minyobates bombetes of Colombia. Unlike most of the dendrobatid alkaloids, which are apparently acetogenins, 1 is clearly terpene-derived. We report the first total synthesis, and thus structural confirmation, of 1, based on the retrosynthetic analysis illustrated. The most critical observations in this synthesis are that both the Rh-mediated cyclization of 4 and the anionic cyclization of 2 can be effected with excellent diastereoselectivity. '5
Scheme 1
PH ACo2CH3
i
1. LDA; Et-I w
2. LiAlHd
53%
2
3
P
2. Brz i CH30H
3. acetone I H+
5
1. 03;Ph3P
78%
6
1. NaH, 2. DBU, ArS02N3
4
,; 9
C
oxo
11
OH 'OB"
1
1. LIAIH4
*fl
Rh octanoate
2. PhCHzBrI NaH
(cat.) 2
89%
CH30pC
75%
ea
1. H'iH20 ____)
2. TsCl I py
Bn0
3
9
Preparation of the C Ring. For the proposed convergent assembly to succeed, it was necessary to prepare both the carbocyclic C ring and the piperidine A ring in high enantiomeric purity. While a variety of approaches to enantiomerically pure cyclopentanes have been developed,* none of these is readily applicable to the preparation of such a highly substituted Abstract uublished in Advance ACS Abstracts. Mav 15. 1995. (1) Spande,.T. F.; Garraffo, H. M.; Yeh, H. J. C:; Pu,'Q. L.; Pannell, L. K.; Daly, J.W. J. Nat. Prod. 1992, 55, 822. (2) For altemative methods for the enantioselective construction of highly substituted cyclopentanes, see: (a) Allan, R. D.; Johnston, G . A. R.; Twitchin, B. Aust. J. Chem. 1979,32, 2517. (b) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. Synthesis, 1981, 74. (c) Klunder, A. J. H.; Huizinga, W. B.; Sessnik, P. J. M.; Zwanenburg, B. Tetrahedron Lett. 1987, 28, 357. (d) Trigalo, F.; Buisson, D.; Azerad, R. Tetrahedron Lett. 1988, 29, 6109. ( e ) Henly, R.; Elk, C. J. J.; Buser, H. P.; Ramos, G.; Moser, H. E. Tetrahedron Lett. 1993, 34, 2923. @
66%
4
F
BnO
3
cyclopentane as 3. We therefore investigated the Rh-mediated c y ~ l i z a t i o nof ~,~ diazoester 4 (Scheme 1). We were attracted to this approach by the our alreadyestablished preparation5 of the enantiomerically pure ,!?-hydroxy ester 5 (two steps from the inexpensive 6-methyl-5-heptene-2(3) For the first observation of the efficient cyclization of simple a-diazo esters, see: Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org. Chem. 1992, 57, 436. (4) For leading references to Rh-mediated intramolecular C-H insertion, see: (a) Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A,; van Basten, A.; Muller, P.; Polleux, P. J. Am. Chem. SOC. 1994, 116, 4507. (b) Wang, P.; Adams, J. J. Am. Chem. SOC. 1994, 116, 3296. (c) Doyle, M. P. In Homogeneous Transition Metal Catalysts in Organic Synthesis; Moser, W. R., Slocum, D. W., Eds.; ACS Advanced Chemistry Series 230; American Chemical Society: Washington, DC, 1992; Chapter 30. (d) Taber, D. F. Comprehensive Organic Synthesis, V. 3; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; p 1045. (5) Taber, D. F.; Silverberg, L. J.; Robinson, E. D. J. Am. Chem. SOC. 1991, 113, 6639.
0002-7863/95/1517-5757$09.00/00 1995 American Chemical Society
5758 J. Am. Chem. SOC., Vol. 117,No. 21. I995
Taber and You
Scheme 2
-2 0
OMe 88
0 OM0
d
8b
-2
of the intermediate Rh carbene with the target C-H bond is rapid and reversible. We reasoned that bridging the 1,3-diol with the acetonide protecting group could provide a rigidity to these transition states. Considering each of the diastereomenc transition states in turn, 4a seemed the most favorable. Transition state 4b looks very much like 4a, with, however, an additional destabilizing buttressing interaction between the methyl group and the ester. In transition state 4c, the Rh dimer, swung out of the way in 4a and 4b, is tucked up in a sterically more congested area under the ring. Transition state 4d has the same problem, and also adds the buttressing between the methyl group and the ester seen in 4b." In fact, the cyclization of 4 proceeded smoothly, to give Sa as the only ("C NMR) diastereomer observed. The relative configuration of Sa was assigned by a combination of COESY and NOE techniques. The most significant observations were a 4.1% NOE between the methyl group and the equatorial H at C-7 and a 5.7% NOE hetween the methyl group and the H at C-2. The lack of an NOE between the ring fusion H's confirmed the trans ring fusion. Given the rigid nature of the chair conformation of the six-membered ring, these observations then secure the relative configuration of Sa. 4.1%
n
"*OM,
8.2
88
one, 90%overall yield and 97% ee, by Ru BINAP hydrogenation6 of the intermediate fl-ketcester). Alkylation' of the dianion proceeded to give the expected anti product, which was reduced and protected to afford 6. Ozonolysis of the alkene 6 followed by oxidation8 gave the ester 7. Evans reported traces of diazo transfer on reaction of 4-nitrobenzenesulfonylazide with an ester e n ~ l a t e . We ~ have found that initial benzoylation of the ester enolate substantially increases the yield of the subsequent diazo transfer. This is the first practical procedure for direct diazo transfer to an ester.'O Cyclization of 4 could proceed to a give a mixture of one or more of the diastereomers Sa-Sd (Scheme 2). There are four corresponding diastereomeric transition states, 4a-4d, leading to cyclization. Previous work on Rh-mediated intramolecular C-H i n ~ e r t i o n ~ ~ s u p p othe r t s concept that initial complexation (6) (a) Noyori, R.: Ohkuma, T.; Kitamura. M.: Takaya, H.: Sayo, N.; Kumobayashi, H.; Akutagawa. A. J. Am. Chem. Soc. 1987, 109, 5856. (b) Kitamura, M.: Ohkuma, T.: Inone, S.: Sayo, N.: Kumobayashi. H.: Akutagawa, A.: Ohta, T.; Takaya, H.: Noyori. R. J. Am. Chem.Soc. 1988, 110. 629. (c) Kitamura, M.; Ohkuma, T.: Takaya, H.: Noyori, R. Tetrahedron Lett. 1988, 29, 1555. (d) Nishi, T.: Kitamura, M.: Ohkuma, T.; Noyori, R. Tetrahedron Len. 1988.29.6327, (e) Schreiber,S . L.; Kelly. S. E.: Porco, 1. A,; Sammakia, T.; Suh, E. M. J. Am. Chem. Soc. 1988, 110,6210. (0 Noyori, R.: Ikeda. T.; Ohkuma, T.: Widhalm, M.; Kitamura, M.: Takaya, H.: Akutagawa, S.; Sayo. N.: Saito. T.: Taketomi. T.; Kumobayahi. H. J. Am Chem: Soc. 1989. 111, 9134. ( 8 ) Jones, B. A,; Yamaguchi. M.; Patten, A,: Danishefsky, S. 1.; Ragan, 1.A.; Smith, D.B.; Schreiber, S. L. J. 018.Chem. 1989, 54, 17. (h) Oppolzer, W.; Wills, M.; Starkmann, C.; Bemardinelli, G . Terrohedron Lett 1990,31, 4117.
Reduction of the ester and subsequent protection led to 9. Monotosylation of the derived diol then gave 3, in 12 steps and 14% overall yield from 5. Using this approach, we have routinely prepared gram quantities of enantiomerically pure 3. Preparation of the Piperidine A Ring. To pursue the proposed convergent assembly of 1, we also needed gram quantities of the enantiomerically pure piperidine 14 (Scheme 3). This was conveniently available starting with the Sharpless asymmetric epoxidationI2 of geraniol 10. Reduction of the epoxide (92%ee) following the Hutchins procedure" proceeded cleanly to give the 2-hydroxycitronellol 11,14 which on periodate cleavageI5 followed by reductive workup gave norcitronellol 12. We have found this assembly of 12 to he much more convenient than alternative chiral auxiliarybased methods. (7) A 95:5 ratio is reponed for the alkylation of an analogous &alkoxy ester enolate: Frater, G. Helv. Chim: Acta 1979, 62, 2825. We have not yet been able to isolate or characterize the very minor diastereomer of 7. The yield reported for 7 is for diastereomerically pure ( I T ) material. (8) Williams, D. R.; Klingler, F. D.: Allen, E. E.: Lichtenthaler, F. W. Tetrahedron Left. 1988, 29, 5087. (9)Evans. D. A,: Britton, T. C.; Ellman, 1. A,: Dorow, R. L. J. Am: Chem. Soc. 1990, 112, 4011. (IO) For an overview of diazo transfer chemistry, see: (a) Re&, M.: Maas, G . Diazo Compoundr: Properties and Synthesis: Academic Press: Orlando, 1986. (b) Askani, R Taber, D. F. Comprehensive Organic Synthesis, Vol. 6: Winterfeldt, E., Ed.: Pergamon: Oxford, 1991; p 103. ( I 1) We have developed a computational approach that rationalizes both the highly diastereoselective cyclization of 4 and the similarly diastereaselective cyclization of other substituted a-diazo esters. We will describe
(14) Taber, D. F.: Houze, J. B. J. Org. Chem. 1994, 59, 4004. (15) Daumas, M.; Vo-Quang.Y.;Vo-Quang,L.: Le Goffic. F. Synthesir
1989.64
Synthesis of the Dendrobatid Alkaloid 251F
J. Am. Chem. Soc., Vol. 117, No. 21, 1995
Ozonolysis of the unstable azide 13 followed by phosphonate condensation and reduction of the azidet6 at -50 OC afforded 14 and 15 in a ratio of 5.6:l. Assignment of the relative configuration of 14 and 15 was made by comparison of 'H NMR chemical shifts with those for known substituted piperidines.I7 At 0 "C, the same cyclization proceeded to give 14 and 15 in a ratio of 1.1:l. Convergent Assembly of 1. Alkylation of 14 with 3 proceeded smoothly to give 16. ?here were then two uncertainties to be faced in approaching the proposed intramolecular alkylation to close the B ring. First, it would be necessary to purify the unstable amino henzenesulfonate derived from 16. Even if the henzenesulfonate could he sufficiently purified, the attempted enolate formation might result instead in p-elimination. Direct formation of the cis-fused azetidinium salt was indeed a real hazard. We observed that the isolated yield of the benzenesulfonate dropped off quickly with extended reaction time. Nevertheless, rapid preparation and purification allowed the isolation of the desired benzenesulfonate. Still's demonstration18 tbat it is possible to generate and alkylate the enolate of a &amino ester made cyclization plausible. The question of the relative configuration of the newly-established stereogenic center remained. We reasoned that transition state 18 would be less congested than 19, so 17 would he favored over 20. While cyclization proceeded smoothly, to give 17 as a single dominant diastereomer, it is not impossible that any of ester 20 that formed could have been equilibrated to 17 under the conditions of the cyclization.
18
20
To complete the synthesis, it was necessary to convert the ester to a methyl group. Several method^'^ have been put forward for effecting this transformation. We have developed what promises to be an efficient alternative. Thus, ester 17 was (16) Knouzi. N ; Vaultier, M.; Toupet. L.; Came, R. Tetrahedron Lett. 1987 28 1757 -.. ,~
(17)Cahill. R.; Crabb, T. A. Org. Magn. Reron. 1912, 4, 259. (18) For an earlier use of a /%aminoester enolate in synthesis, see: Still, W. C.: M. 1. .I. Am. C.h r m ~Tor~.1977 99, 94R ~, Schneider. ~~, .. , ., (19) For a review of methods for the deoxygenation of alcohols, see: (a) Hartwig, W. Tetrahedron 1983, 39, 2609. For additional procedures for the deoxygenation of a primary alcohol to a methyl group, see: (b) Barton, D. H. R.: Mothenuell. W. B,.; Stange, A. Synthesir 1981, 743. (c) Trost, B. M.; Renaut, P. J. Am. Chem. Soc. 1982, 104, 6668. (d) Grether, G.;Mitt. T.; Williams, T. H.; Uskokovic, M. R. J. Or8. Chem. 1983, 48, 5309. ( e ) Feldman, K. S.; Wu, M.-1.; Rotella. D. P. J. Am. Chem. Sot. 1990, 112, 8490. (0 Barton. D. H. R.; J a g , D. 0.; Jaszberenyi, 1. C. Tetrahedron Lett. 1990, 31, 4681. (8) Banon. D. H. R.: Jang, D. 0.; Jaszberenyi, 1. C. Tetrahedron Lett. 1992, 33, 231 I . (h) Barton. D. H. R.; Jang, D. 0.: Jaszberenyi. 1. C. Tetrahedron Lett. 1990. 31, 4681. ~~~~~
~
~
~~
~~
~~
~~
~~
reduced to the corresponding alcohol, which was then converted to the sulfideJO Dissolving metal reduction2' then effected clean desulfurization as well as debenzylation to give 1. The amino alcohol from the reduction had a mass spectrum congruent with that reported for 1. The identity of the synthetic amino alcohol with the natural alkaloid was confirmed by 'H and I3C NMR,22 GC-MS coinjection on a capillary GC column, and GC-IR.23 By the method of synthesis, we are confident of the absolute configuration of the stereogenic centers at C-3, C-7, C-8, C-12, and C-13 of alkaloid 251F. The centers at C-9 and C-10, on the other hand, are not secured by this synthesis, as ester 17 could he subject to both epimerization and p-elimination. In addition to 1,then, structures 21,22, and 23 could altematively he possible for 251F.
1
21
22
23
17
"S
19
~~
5759
~
,
With five of the seven centers of 251F established, we can r e m to the NOESY spectrum originally recorded for the natural product. The key NOES for our purposes are those observed between the 2-axial H and Hlo and between Hlo and the 9-methyl. The former establishes that Hle is axial, and the latter establishes that the 9-methyl is on the same side of the ring as Hto. Thus, the relative configuration of 251F is confirmed to he 1. The absolute configuration of 1 is as yet unknown. The isolation and structure of 1 was carried out with 300pg of material, the total that had been purified from the Minyobates bombetes extract.' The convergent assembly of 1 outlined here, even in its initial form, has already increased the supply of the purified alkaloid by a factor of more than 100. The high (20) Cleary. D. G.Synth Commun. 1989, 19, 737. (21)For the dissolving metal reduction of .secondap phenyl alkyl thioethers to alkanes, see: (a) Haskell, T. H.; Woo, P. W. K.; Watson, D. R. J. O q . Chem. 1977,42, 1302. (b) Masaki, Y.; Hashimoto, K.; Sakuma. K.; Kaji, K. Tetrahedron Lett. 1982, 23, 1481. ( c ) Sundov. A. F.;Emolenko, M. S.; Yashunsky, D. V.; Borodkin, V. S.; Kochetkov, N. D. Tetrahedron Lctt. 1987, 28. 3835. (22) The 'H and spectra were acquired in D2OlDCI. (23) We thmkT. F. Spande. H. M. Gmaffo, and H. C. 1.Yeh, Laboratory of Bimrganic Chemistry, NIH. for making these comparisons.
5760 J. Am. Chem. Sac., Vol. 117, No. 21, 1995
Tuber and You
Scheme 3 ?OH
1.SAE
2. NaBH3CNI BFs'OEt2 79%
10
K
O
H
Lz:py
OH
~
1 . Ne104;
zN3 2. NaBHo 61%
11
*
s
1. 03;Ph3P
D
?
2. EtOZP-CO,Et 12
78%
13
3. Ph3P I H2O
68%
I
CO2Et 14
15
56%
16
- 4 q - .'4" %h *** 1. LIAIH4
1. BSCl 2. LiHMDS
2. PhS)2 I Bu~P
2. LiHMDS 53% 53%
Et4d Et02d
3. Na I NH3 1
I
OH
diastereoselectivity observed for the cyclization of 4 is especially noteworthy. Our preliminary investigations with additional a-diazo esters indicate that these substrates often cyclize with high diastereoselectivity.' Experimental Section14 Methyl (2S,3S)-2-Ethyl-3-hydroxy-7-methyl-6-octenoate. n-Butyllithium (74 mL, 0.17 mol, 2.31 M in hexane) was added to a stimng solution of diisopropylamine (19 g, 0.18 mol) in THF (150 mL) at -75 "C. After warming up to -50 "C, P-hydroxyester 6 (14.4 g, 77.4 mmol) was added neat, and the temperature was raised to -30 "C. Iodoethane (8.7 mL, 0.1 mol) in HMPA (60 mL) was added, and the reaction mixture was stirred with warming to room temperature over 4 h. Saturated aqueous NKCl(60 mL) was added to quench the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with 30% ethyl acetate/petroleum ether. The combined extract was dried (Na2S04) and concentrated. The residue was chromatographed with 8% ethyl acetate/petroleum ether to give the desired alkylated product (10.8 g, 70% yield) as a pale yellow oil: TLC Rf 0.51 (20% ethyl acetate/petroleum ether); 'H NMR (6) 5.10 (m, 1 H), 3.71 (s, 3 H), 3.69 (m, 1 H), 2.53 (d, J = 8.0 Hz, 1 H), 2.20 (m, 1 H), 1.76 (m, 2 H), 1.71 ( s , 3 H), 1.63 (s, 3 H),1.48 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H); I3CNMR (6) d: 11.8, 17.6, 25.7, 51.5, 52.6, 71.6, 123.7; u: 22.7, 24.3, 35.5, 132.3, 176.0; IR (cm-I) 3465, 1736, 1670, 1437, 1376, 1171; MS ( d z , %) 214 (M+, l), 196 (52), 137 (24), 136 (93), 131 (22), 125 (20), 121 (39), 113 (43), 107 (46), 102 (100); HRMS cald for C12H2203214.1569, found 214.1573; [ a ]=~-12.0. (4S,SR)-2,2-Dimethyl-5-ethyl-S-( 4-methyl-3-pentenyl)-1,3-dioxane 6. Lithium aluminum hydride (2.3 g, 61.0 mmol) was added to a solution of the alkylated P-hydroxyester (6.1 g, 30.5 mmol) in THF (75 mL). The reaction mixture was heated to reflux for 10 h and then cooled to 0 OC. H2O (3 mL), aqueous 10% NaOH (3 mL), and HzO (9 mL) were added sequentially to the grayish reaction mixture over a period of 1 h. Substantial gas and heat evolution were observed, and the reaction mixture turned into a white paste. The reaction mixture was filtered, and the filtrate was concentrated to give the desired crude diol (5.6 9); 'H NMR (6) 5.17 (m, 1 H),3.91 (m, 1 H),3.69 (m, 2 H),
3.03(brs,lH),2.82(brs,lH),2.11(m,2H),1.73(s,3H),1.65(s, 3 H), 1.60 (m, 2 H), 1.41 (m, 3 H), 0.96 (t, J = 7.4 Hz, 3 H); I3C NMR (6) d: 11.6, 17.6, 25.0, 46.0, 75.5, 123.9; u: 21.4, 24.4, 35.5, 63.6, 132.3. p-Toluenesulfonic acid monohydrate (1.2 g, 6.1 mmol) was added to a stimng solution of the crude diol (5.6 g) in dimethoxypropane (70 mL). After 0.5 h, N a C 0 3 (1.3 g, 15.3 mmol) was added to neutralize the reaction mixture. The reaction mixture was filtered, and the filtrate was concentrated and chromatographed directly to give 7 (5.8 g, 53% yield from 6 ) as a pale yellow oil: TLC Rf 0.89 (10% ethyl acetate/ petroleum ether); IH NMR (6) 5.09 (m, 1 H), 3.86 (dd, J = 5.0, 6.5 Hz, 1 H),3.51 (m, 2 H), 2.18 (m. 2 H),1.68 (s, 3 H), 1.61 (s, 3 H), 1.40 (d, J = 3.6 Hz, 6 H), 1.38 (m, 2 H), 1.07 (m, 2 H), 0.86 (t, J = 7.3 Hz, 3 H); I3C NMR (6) d: 10.9, 17.8, 19.3, 25.7, 29.5, 40.4, 72.5, 124.3; u: 21.0, 23.4, 33.1, 64.0, 97.9, 131.5; IR (cm-I) 2926, 2859, 1457, 1379, 1264, 1199; MS (dz,%) 226 (M', 3), 211 (M' - CH3, 20), 168 (55), 150 (50), 135 (48). 121 (88), 111 (loo), 109 (52), 107 (29); HRMS cald for C14H2602 226.1934 (21 1.1699 loss of CH3), found 21 1.1695. Methyl (4S,5R)-2,22-Dimethyl-5-ethyl-l,3-dioxanepropionate 7. A stream of ozone was passed through a solution of 6 (5.4 g, 24.1 mmol) in CH2C12 (250 mL) at -75 "C. After 20 min, the red indicator (Sudan Red) was decolorized, and the ozone was tumed off. The reaction mixture was flushed with N2, and triphenylphosphine (7.6 g, 28.9 mmol) was added. The mixture was allowed to warm to room temperature over 10 h. The reaction mixture was then concentrated, and the residue was dissolved in 1:9 H20/CH3OH (60 mL). NaHCO3 (40 g, 0.48 mol) and Br2 (5 mL, 96.3 mmol, 1.95 M in 1:9 HzOKH3OH) were added sequentially to the reaction mixture, tuming the mixture bright orange. After stimng for 10 min, Na2SzO4.5H20 (36.0 g, 0.14 mol) was added. The orange reaction mixture decolorized instantly with evolution of gas. The reaction mixture was partitioned between ether and brine. The combined ethereal layer was dried (Na2S04), concentrated, and chromatographed to give the ester 7 (4.3 g, 78% yield from 7) as a colorless oil: TLC Rf 0.68 (20% ethyl acetate/petroleum ether), [ a ] ~ = -54.4; IH NMR (6) 3.88 (dd, J = 6.0, 6.5 Hz, I H), 3.68 (s, 3 H), 3.52 (m, 2 H),2.43 (m, 2 H), 2.07 (m, 1 H), 1.68 (m, 1 H), 1.49 (m, 1 H), 1.36 (d, J = 6.2 Hz, 6 H),1.09 (m, 1 H), 0.87(t, J = 7.3 Hz, 3 H); I3C NMR (6) d: 10.9, 19.3, 29.4, 40.4, 51.4, 72.4; u: 20.9, 28.3, 29.7, 63.9,98.0, 174.3. IR (cm-I) 2965, 1740, 1438, 1380, 1201, 1165, 1124, 868; MS (dz,%) 215 (M+- CH3,45), 172 (lo), 156 (7), 155 (71), 141 (52), 140 (21), 123 (loo), 117 (92), 113 (29), 111 (60), 110 (251, 101(7); HRMS cald for C12H2204 230.1518 (215.1284 loss of CH3), found 215.1279. Anal. Calcd for C12H2204: C, 62.58, H, 9.63. Found: C, 62.89, H, 9.76. Methyl (4S,5R)-a-Diazo-2,2-dimethyl-S-ethyl-1,3-dioxanepropionate 4. Sodium hydride (0.6 g, 15 mmol, 60% in mineral oil), methyl benzoate (1.36 g, 10.0 mmol), and 2 drops of CH30H were added sequentially to an ice-cold solution of ester 7 (1.15 g, 5.0 mmol) in DME (25 mL). The grayish mixture was heated to reflux for 13 h, during which time it turned dark brown. Aqueous acetate buffer (7 mL, 0.25 M, pH = 5 ) was added to the reaction mixture, followed by ether (15 mL). The organic layer was separated, and the aqueous layer was extracted with 30% ethyl acetate/petroleum ether (3 x 20 mL). The combined organic extract was dried (NaS04), concentrated, and chromatographed to give the benzoyl ester (1.5 g, 93% yield) as a yellow oil: TLC Rf0.42 (20% ethyl acetate/petroleum ether); 'H NMR (6) 8.14-7.23 (m, 5 H), 3.86 (m, 1 H), 3.70 (d, J = 13.1 Hz, 3 H), 3.70-3.37 (m, 2 H), 2.70-2.41 (m, 1 H), 2.07-1.78 (m, 1 H), 1.48 (m, 2 H), 1.34-1.23 (dd, J = 9.8, 11.7 Hz, 6 H), 1.09 (m, 2 H), 0.91 (t. J = 7.4 Hz, 3 H). DBU (1.3 mL, 8.6 "01) and p-nitrobenzenesulfonylazide (2.0 g, 8.6 mmol) were added sequentially to a solution of the benzoyl ester (1.4 g, 4.4 mmol) in CHzClz (20 mL) at 0 "C. After warming to room temperature (0.5 h), the reaction mixture was quenched with aqueous phosphate buffer (13 mL, 0.5 M, pH = 7). The CHzClz layer was separated, and the aqueous layer was extracted with CHzCl2 (3 x 20 mL). The combined organic extract was dried (NazS04), concentrated, and chromatographed to give 4 (1.4 g, 78% from 7) as a bright yellow oil, TLC Rf 0.43 (10% ethyl acetate/petroleum ether); 'H NMR (6) 3.89 (dd, J = 5.1, 6.6 Hz, 1 H), 3.76 (s, 3H), 3.74 (m,'l H), 3.56 (t, J = 11.0 Hz, 1 H), 2.68 (dd, J = 5.3, 6.1 Hz, 1 H), 2.41 (dd, J = 7.0, 8.2 Hz, 1 H), 1.56 (m, 4 H), 1.55 (d, J = 9.7 Hz, 6 H), 0.89 (t, J = 7.4
Synthesis of the Dendrobatid Alkaloid 251F Hz, 3 H); 13CNMR (6) d: 27.6, 36.1,46.1, 56.0, 58.6, 90.1, 144.0; u: 37.7,43.6, 80.5, 114.9, 185.0; IR (cm-I) 2960,2078, 1699, 1437, 1221; MS (d~, %) 228 (M+ - N2.3), 213 (19), 198 (74), 197 (24), 183 (6), 140 (13), 117 (100); HRMS cald for C12H200& 256.1424 (228.1362 loss of N2); found 228.1366.
J. Am. Chem. SOC.,Vol. 117, No. 21, 1995 5761
with CH2C12 (3 x 20 mL). The combined organic extract was dried (NaS04), concentrated, and chromatographed to give the monotosylated product 3 (1.22 g, 66% from 9) as a colorless oil: TLC Rf0.28 (35% ethyl acetate/petroleum ether); 'H NMR (6) 7.77 (d, J = 8.2 Hz, 2 H), 7.31 (m, 7 H), 4.48 (s, 2 H), 4.07 (m, 3 H), 3.39 (m, 2 H), 2.45 (s, 3 Methyl [lS,2S,3aS,7aR]-1,5,5-Trimethyl-4,6-dioxa-(2,3,3a,4,5,6, H), 2.17 (br, s, 1 H), 1.95 (m, 1 H), 1.75 (m, 2 H), 1.40 (m, 1 H), 1.25 ( t , J = 6 . 1 H z , 1 H ) , 0 . 9 7 ( d , J = 6 . 5 H z , 3 H ) ; I 3 C N M R ( 6 ) d : 18.3, 7,7a)octahydroindene-2-carboxylateSa. CH2Cl2 (40 mL) was passed 21.5, 37.2, 44.0, 55.2, 73.5, 127.4, 127.8, 128.3, 129.8; u: 23.3, 70.1, through a pad of K2CO3 into the bright yellow diazo ester 4 (2.1 g, 8.2 72.8, 73.0, 123.8, 138.5, 144.8; IR (cm-l) 3454, 3012, 1483, 1375, mmol). A catalytic amount of Rh2Oct (0.9 mg, 1.16pmol) was added 1189, 654. to the reaction mixture. The mixture was decolorized instantly with evolution of gas. After the gas evolution had ceased (5 min), the (2S)-2,6-DimethyM-hepten-l-o112. A solution of sodium periomixture was concentrated and chromatographed directly to give a single date (20 g, 93.6 mmol in 104 mL of H2O) was added to a suspension diastereomer Sa (1.8 g, 89% yield from 4) as a pale yellow oil, TLC of 60-200 mesh Si02 (43 g) in CHzClz (250 mL) at room temperature. Rf0.38 (10% ethyl acetate/petroleum ether). The absolute and relative After the mixture was thoroughly stirred, diol 11 (13.4 g, 77.8 mmol) configuration was established by NOE experiment: IH NMR (6) 3.89 was added to the Si02 suspension. After stirring for 5 min, the (dd, J = 5.1, 6.5 Hz, 1 H), 3.80 (m, 2 H), 3.61 (s, 3 H), 2.44 (m, lH), suspension was filtered, and the filtrate was added directly into a stirring 2.26 (m, 1 H), 1.81 (m, 2 H), 1.42 (d, J = 8.9 Hz, 6 H), 1.31 (m, 1 H), solution of N a B h (3.6 g, 93.6 mmol) in CH3OH (200 mL) at 0 "C. 1.16 (d. J = 7.6 Hz, 3 H); I3C NMR (6) d: 18.3, 19.7, 29.7, 36.9, After 15 min, the reaction mixture was diluted with ethyl ether (60 47.0,49.1,51.9,73.8; u: 32.7, 65.5,99.5, 176.6; IR (cm-I) 2954, 1735, mL) and quenched with aqueous 10% HCl(40 mL). The organic layer 1459, 1381, 1264, 1178, 1113;MS(m/z,%)213(M+-CH3,42), 153 was separated, and the aqueous layer was extracted with 40% ethyl ( l l ) , 139 (33), 127 (30), 121 (21), 111(49), 93 (100); HRMS cald for acetate/petroleum ether (3 x 100 mL). The combined organic phase CI~HZO 228.1362 O~ (213.1127 loss of CH3), found 213.1132. was dried (Na2S04), concentrated, and chromatographed to give 12 [lS,2S,3aS,7aR]-1,5,5-T~ethyl-2-phenylmethoxymethyl-4,6-di-(6.74 g, 61% yield from 11) as a colorless oil: TLC Rf 0.51 (10% oxa-(2,3,3a,4,5,6,7,7a)-octahydroindene9. Lithium aluminum hydride ethyl acetate/petroleum ether); 'H NMR (6) 5.13 (m, 1 H), 3.48 (ddd, (0.7 g, 18.1 mmol) was added to an ice-cold solution of Sa (l.O3g, 4.5 J=6.3,7.1,8.4Hz,2H),2.01(m,2H),1.69(~,3H),1.66(m,lH), 1.61 (s, 3 H), 1.44 (m, 1 H), 1.17 (m, 1 H), 0.89 (d, J = 6.9 Hz, 3 H); mmol) in THF (40 mL). The reaction mixture was brought to reflux I3C NMR (6) d: 16.5, 17.6, 25.7, 35.3, 124.5; u: 25.4, 33.2, 68.3, for 10 h before being chilled to 0 "C. H20 (1.0 mL), aqueous 10% 131.4; IR (cm-I) 3346, 2922, 1673, 1454, 1377, 1041, 826; MS ( d z , NaOH (1.0 mL), and H20 (3.0 mL) were added sequentially over 2 h. The grayish reaction mixture was tumed into a white paste. This white %) 142 (M+, 23). 110 (5), 109 (48), 96 (4), 95 (39), 85 (4), 82 (79), 81 paste was filtered, and the filtrate was concentrated to give the crude (33), 71 (25), 69 (100); HRMS cald for CgH180 142.1358, found 142.1355; [ a ]=~-9.4. alcohol (0.86 8): IH NMR (6) 4.0 (dd, J = 3.8, 6.5 Hz, 1 H), 3.773.43 (m, 4 H), 1.89 (br s, 1 H), 1.84 (m, 3 H), 1.45 (d, J = 5.8 Hz, 6 (2S)-l-Azido-2,6-dimethy1-5-heptene 13. Pyridine (40 mL) and H), 1.39 (m, 2 H), 1.08 (d, J = 6.1 Hz, 3 H). toluenesulfonyl chloride (22.5 g, 0.12 mol) were added to a stirring Sodium hydride (0.5 g, 12.9 mmol) was added to a stirring solution solution of alcohol 12 (12.9 g, 91.0 mmol) in CH2C12 (160 mL) at of the above crude alcohol (0.86 g) in THF (20 mL). After stirring room temperature. After 10 h, the reaction mixture was quenched with for 20 min at room temperature, benzyl bromide (0.71 g, 6.0 mmol), aqueous 10% HCl(lO0 mL) and washed with saturated aqueous NH4and tetrabutylammonium iodide (0.16 g, 0.4 mmol) were added to the C1 (50 mL). The CHzCl2 layer was separated, and the aqueous layer reaction mixture. After 10 h at room temperature, saturated aqueous was extracted with CHzCl2 (3 x 150 mL). The combined CH2C12 extract was dried (NazSOd), concentrated and chromatographed to give NaCl (10 mL) was added. The organic phase was separated, and the aqueous phase was extracted with 30% ethyl acetate/petroleum ether the desired tosylate (24.7 g, 92% yield) as a pale white oil: TLC Rr (3 x 20 mL). The combined organic extracts was dried (KZC03), 0.71 (10% ethyl acetate petroleum ether); 'H NMR (6) 7.79 (d, J = concentrated, and chromatographed to give 9 (0.93 g, 75% yield from 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 5.01 (m, 1 H), 3.86 (m, 2 H), Sa) as a pale yellow oil: TLC Rf 0.64 (20% ethyl acetate/petroleum 2.23 (s, 3 H), 1.77-1.96 (m. 3H), 1.67 (s, 3H), 1.54 (s, 3 H), 1.38 (m, ether); 'H NMR (6) 7.33 (m, 5 H), 4.49 (s, 2 H), 3.98 (dd, J = 3.9.6.8 1 H), 1.12 (m, 1 H), 0.89 (d, J = 6.9 Hz, 3 H); 13CNMR (6) d: 16.3, Hz, 1 H), 3.71 (m, 2 H), 3.40 (m, 2 H), 1.84 (m, 3 H), 1.41 (d, J = 5.2 17.5,21.5, 25.6, 32.3, 123.8, 127.8, 129.7; u: 24.9, 32.6, 131.8, 133.1, Hz, 6 H), 1.38 (m, 2 H), 1.16 (d, J = 6.1 Hz, 3 H); I3C NMR (6) d: 144.6. 18.1, 19.7, 29.8, 35.1, 43.0, 49.4, 73.8, 127.4, 127.5, 128.3; u: 32.8, Sodium azide (7.8 g, 0.12 mol) was added to a stirring solution of 65.8,73.1,73.6, 99.2, 138.6; IR (cm-I) 3008, 2925, 2854, 1454, 1365, the tosylate (7.1 g, 24.0 mmol) in DMF (80 mL). After stirring at 60 1265, 1197, 1095, 742, 698; MS (dz%) , 275 (M' - CH3, 34), 141 OC for 10 h, the white orange reaction mixture was diluted with ether (35), 125 (18), 123 (17), 111 (loo), 110 (17), 109 (19), 108 (23), 107 (30 mL) and quenched with saturated aqueous NaCl (60 mL). The (79), 105 (18); HRMS cald for C18H2603 290.1882 (275.1647 loss of mixture was partitioned between ether and brine. The combined CH3), found: 275.1643. ethereal extract was dried (&CO3), concentrated, and chromatographed (lS,2R,3R,4S)-3-Methyl-2-(4-methylbenzylsulfonyloxy methyl)to give 13 (3.40 g, 78% yield from 12) as a pinkish oil: TLC Rf 0.56 4-(phenylmethoxy)cyclopentanol 3. p-Toluenesulfonic acid mono(25% CHzCldpetroleum ether); 'H NMR (6) 5.11 (m, 1 H), 3.21 (dq, hydrate (0.09 g, 0.46 mmol) was added to a stirring solution of 9 (1.32 J = 5.8, 10.3 Hz, 2 H), 1.98 (m, 2 H), 1.77 (m, 1 H), 1.71 (s, 3 H), g, 4.6 mmol) in CH3OH (20 mL). After 20 min at room temperature, 1.60 (s, 3 H), 1.44 (m, 1 H), 1.21 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3 H); the reaction mixture was neutralized with NaHC03 (1.9 g, 22.9 mmol). I3C NMR (6) d: 17.5, 17.6, 25.7, 33.1, 124.1; u: 25.2, 34.1, 57.8, The suspension was filtered, and the filtrate was concentrated and 131.6; IR (cm-l) 2926,2098, 1451, 1379, 1281; MS ( d z ,%) 139 (M+ chromatographed to give the desired diol (1.10 g, 96% yield from 9) - N2, 3), 138 (19), 125 (9), 124 (loo), 111 (15), 110 (10); HRMS as a colorless oil: TLC Rf 0.28 (5% CH~OWCH~C~Z); 'H NMR (6) cald for C ~ H I ~ 167.1424 N ~ (139.1362 loss of Nz), found 139.1386. 7.34(m,5H),4.51(~,2H),4.08(q,J=7.1Hz,lH),3.82(dd,J= Ethyl (2R,5S)-5-Methylpiperidineacetate 14. A stream of ozone 5.1, 6.5 Hz, 1 H), 3.40 (m. 3 H), 2.43 (br s, 2 H), 2.01-1.87 (m, 3 H), was passed through a solution of azide 13 (4.1 g, 24.6 mmol) in CHz1.60 (m, lH), 1.31 (m, 1 H), 1.14 (d, J = 6.8 Hz, 3 H); I3C NMR (6) C12 (240 mL) at -75 "C until the solution turned pale blue (21 min). d: 18.7, 37.2, 44.1, 57.2, 76.6, 127.5, 128.3; u: 37.1, 64.9, 73.0, 73.2, The ozone was turned off, and the reaction mixture was flushed with 138.5; IR (cm-I) 3374 (br), 3030, 2868, 1658, 1496, 1454, 1364,737, N2. Triphenylphosphine (6.4 g, 24.6 mmol) was added, and the reaction 698; MS ( d z ,%) 216 (M+ - 2 OH, 17), 215 (loo), 197 (24), 185 mixture was allowed to warm to room temperature over 4 h. The (15), 144 (8),129 (17), 155 (10); HRMS caldfor CisH2203: 250.1569, reaction mixture was concentrated and added to an ice-cold solution found 250.1576. of ylide preparing from the addition of NaHMDS (29 mL, 29 mmol, p-Toluenesulfonyl chloride (1.0 g, 5.3 mmol) and pyridine (0.5 mL, 1.0 M in THF) to triethylphosphonoacetate (6.6 g, 29.5 mmol) in THF 5.7 mmol) were added to a stimng solution of the diol (1.1 g, 4.4 mmol) (70 mL). After stirring at room temperature for 1.5 h, the reaction in CH2C12 (20 mL). After 18 h at room temperature, aqueous 10% mixture was chilled to -60 "C. Triphenylphosphine (6.4 g, 24.6 mmol) HCl(6 mL) followed by saturated aqueous N&Cl (10 mL) were added. and H20 (0.6 mL) were added, and the reaction mixture was allowed The CHzClz phase was separated, and the aqueous phase was extracted to warm to room temperature over 13 h. After the reaction mixture
5762 J. Am. Chem. Soc., Vol. 117, No. 21, 1995 was quenched with saturated aqueous NaHCO3 (6 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic extract was dried (Kzco3), concentrated and distilled bulb-to-bulb (bp 1.0- = 98 "C) to give a mixture of the trans-14 and cis-15piperidine esters in a ratio of 5.6: 1 (by 'H NMR integration and quantitative I3C)(3.09 g, 68% yield from 13) as a yellow oil. This mixture of diastereomers was then chromatographed, eluting with 10% CH30WCHZC12, to give transester 14 (2.62 g, 58% yield from 13) and cis-ester 15 (0.47 g, 10% yield from 13)both as white crystals. 14: TLC Rf0.37 (10% CH30WCHzClz); mp = 172 OC; IH NMR
Taber and You
H), 3.41 (dd, J = 6.8, 2.1 Hz, 1 H), 2.80 (d, J = 12.1 Hz, 1 H). 2.65 (d, J = 10.1 Hz, 1 H), 2.26-1.46 (m, 13 H), 1.45-1.21 (m, 2 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.01 (d, J = 5.9 Hz, 3 H), 0.83 (d, J = 6.0 Hz, 3 H); I3C NMR (6) d: 14.4, 18.0, 19.6, 30.8, 36.8, 40.7, 46.4, 47.2, 53.4, 62.8, 127.3, 127.4, 128.2; u: 30.9, 32.2, 32.8, 54.9, 60.1, 64.6, 73.1,75.1, 138.9, 175.2; IR (cm-I) 3029,2929, 1728, 1454, 1375, 1098, 735,697; MS ( d z , %) 398 (M' - H', 2), 370 (2), 354 (3), 309 (20), 308 (100). 278 (4), 264 (3), 234 (3), 206 (3), 192 (3). 164 (2), 152 (lo), 150 (3,148 (6), 136 (3), 124 (2), 111 (27), 110 (7). 107 (5); HRMS cald for Cz~H3703N399.2773, found 399.2742 Thiol Ether. Lithium aluminum hydride (21.1 mg, 0.56 "01) was (6)4.38(brs,lH),4.12(q,J=7.1Hz,2H),3.13(m,lH),2.93(m,added to a stirring solution of 17 (52.1 mg, 0.13 mmol) in THF (1.0 1 H), 2.55 (m, 2 H), 2.27 (t, J = 11.5 Hz, 1 H), 1.80-1.58 (m, 3 H), mL). After stirring at 50 OC for 3 h, the reaction mixture was quenched 1.36(m, l H ) , 1 . 2 3 ( t , J = 7 . 1 H z , 3 H ) , 1.19-0.99(m, lH),0.85(d, sequentially with H20 (0.02 mL), 10% aqueous NaOH (0.02 mL), and J = 6.6 Hz, 3 H); I3C NMR (6) d: 14.1, 19.2, 30.7, 53.1; u: 31.5, H20 (0.06 mL). The grayish reaction mixture tumed into a white paste. 32.8,40.4,53.5,60.5, 171.7; IR (cm-I) 3341, 2927, 1732, 1460, 1375, The resultant suspension was filtered, and the filtrate was concentrated 1337, 1176, 1033; MS ( d z , %) 185 (M+, 2), 156 (6), 142 (2), 138 to give the crude alcohol: 'H NMR (6) 7.34 (m, 5 H), 4.48 (s, 2 H), (13), 129 (22), 110 (12), 99 (27), 98 (100); HRMS cald for 3.70(dd,J=4.3,5.1 Hz,2H),3.54(m,2H),3.36(m,2H),2.77(br C I O H I ~ O ~185.1416, N: found 185.1421; [ a ] ~-6.5. = s, 1 H), 2.24-1.16 (m, 15 H), 1.08 (d, J = 6.3 Hz, 3 H), 0.81 (d, J = 15: TLC Rf0.32 (10% CH3OWCHzC12); 'H NMR (6) 4.12 (q, J = 6.1 Hz, 3 H). 7.1Hz,2H),3.71(s,1H),3.32(m,2H),2.90(dt,J=6.1,16.4Hz, The crude alcohol residue was dissolved in DME (1.O mL), and the 1 H), 2.72 (m, 2 H), 2.04-1.83 (m, 3 H), 1.37 (m, 2 H), 1.29 (t. J = phenyl disulfide (80.3 mg, 0.38 mmol) and n-tributylphosphine (81.0g, 7.1 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3H); I3C NMR (6) d 14.1, 17.6, 0.38 mmol) were added. The mixture was maintained at reflux for 8 28.6, 52.1; u: 28.0, 28.6, 39.5, 50.6, 60.5, 172.0. h and then cooled to room temperature. The mixture was diluted with Amino Alcohol 16. Tosylate 3 (0.35 g, 0.87 mmol) and BL@I (0.06 ether (4 mL) and quenched with saturated aqueous NaCl(2 mL). After g, 0.16 mmol) were added to a refluxing solution of trans-piperidine the organic phase was separated, the aqueous phase was extracted with ester 14 (0.18 g, 0.97 mmol) and K2CO3 (0.19 g, 1.36 "01) in toluene 50% ethyl acetate/petroleum ether (2 x 4 mL). The combined organic (3 mL). The reaction mixture was maintained at reflux for 3 h, before layer was dried (KzC03), concentrated, and chromatographed to give it cooled to room temperature. The reaction mixture was partitioned the thioether (53.2 mg, 94% yield from 17)as a pale pink oil: TLC Rf between ether and, sequentially, water and brine. The combined organic 0.43 (20% ethyl acetate/petroleum ether); 'H NMR (6) 7.30 (m. 10 extract was dried (K2CO3) and concentrated in vacuo. The oily residue H), 4.49 (s, 2 H), 3.50 (dd, J = 4.2, 4.9 Hz, 1 H), 3.31 (dd, J = 1.8, was chromatographed, eluting with 10% acetone/CHzClZ, to give 16 7.1 Hz, 1 H), 3.01 (dq, J = 3.6, 8.6 Hz, 2 H), 2.73 (m, 2 H), 2.22(0.20 g, 56% yield from 3) as a yellow oil: TLC Rf = 0.18 (10% 1.01 (m, 15 H), 1.02 (d, J = 6.0 Hz, 3 H), 0.79 (d, J = 6.1 Hz, 3 H); acetone/CHzClz); 'H NMR (6) 7.36 (m, 5 H), 4.50 (s, 2 H), 4.15 (q, J I3C NMR (6) d: 17.8, 19.7, 30.6, 37.0, 39.9, 44.6, 46.5, 47.5, 64.0, = 7.1 Hz, 2 H), 3.84 (q, J = 8.1 Hz, 1 H), 3.34 (m, 2 H), 3.01-2.61 175.5, 127.3, 127.5, 128.3, 128.8, 128.9; u: 30.0, 33.1,33.2, 34.8,55.4, (m, 3 H), 2.39-2.11 (m, 3 H), 1.89 (m, 2 H), 1.81-1.29 (m, 9 H), 65.0, 73.0, 134.0, 156.1; IR (cm-I) 3008, 1453, 735, 697; MS ( d z , 1.24(t,J=7.1Hz,3H),1.04(m,1H),1.01(d,J=6.4Hz,3H), %) 449 (M' , 2), 340 (24), 326 (ll), 249 (6), 234 (32), 164 (lo), 152 0.85 (d, J = 6.4 Hz, 3 H); I3C NMR (6) d: 14.2, 18.5, 19.2, 29.2, (22), 11 1 (27), 109 (100). 38.8, 43.4, 52.7, 59.8, 77.9,127.4, 128.3, 128.9; u: 29.9, 31.8, 35.4, Alkaloid 251F 1. Ammonia (15 mL) was condensed with a cold 38.7, 57.6, 60.5, 60.9, 73.0, 73.9, 172.1; IR (cm-I) 3416, 3030, 2925, finger condenser into a stimng solution of the thioether (50.2 mg, 0.14 1733, 1496, 1454, 1367, 1099, 736, 698; MS ( d z , %) 417 (M', l), mmol) in EtOH/THF (3 mL, 2:l by volume) at -78 "C. Sodium metal 331 (22), 330 (94), 326 (3), 328 (2), 224 (ll), 198 (100). 184 (13), (1.7 g, 73.9 mmol) was added to the reaction mixture in portions until 170 (l), 156 (3), 124 (l), 121 (lo), 110 (2); HRMS cald for C2&!the mixture remained dark blue. After 20 min, the reaction mixture NO4 417.2879, found 417.2860; [ a ]=~+26.7. was flushed with N2 and allowed to warm. The residual white solid Tricyclic Amine 17. Pyridine (0.25 mL, 3.12 mmol) and benzenewas partitioned between ethyl acetate and saturated aqueous NKC1. sulfonyl chloride (0.06 mL, 0.46 mmol) were added to a stirring solution The combined organic extract was dried (KzCO,), concentrated, and of 16 (0.13 g, 0.31 mmol) in CH2C12 (2 mL). After 3 h at room chromatographed to give 1 (21.0 mg, 66% yield from 17) as a pale temperature, the reaction mixture was partitioned between CHzClz and, yellow oil: TLC Rf 0.09 (40% acetone/CHzC12);IH NMR in D20 (6) sequentially, saturated aqueous NfiCl and saturated aqueous NaHC03. 3.55(dd,J=6.5,ll.OHz,1H),3.38(d,J=6.5,ll.OHz, 1H),3.31 The combined organic extract was dried (K2CO3) and concentrated in (d, J = 13.4 Hz, 1 H), 3.18 (d, J = 12.2 Hz, 1 H), 3.09 (dd, J = 4.5, vacuo. The yellow residue was chromatographed, eluting with 3% 13.4 Hz, 1 H), 2.56 (td, J = 3.1, 11.3 Hz, 1 H), 2.49 (t, J = 12.4 Hz, acetone/CHzClz,to give the desired benzenesulfonylated product (0.12 1H),2.11(dd,J=3.3,14.6Hz,1H),2.0(m,1H),1.48-1.80(m,4 g, 69% yield from 16)as a pale yellow oil: TLC Rf0.52 (4% acetone/ H), 1.60 (m, 1 H), 1.52 (m, 1 H), 1.30-0.98 (m, 4 H), 0.88 (d, J = 6.4 CH2C12); IH NMR (6) 7.94-7.28 (m, 10 H), 4.60 (m, 1 H), 4.47 (s, 2 Hz, 3 H), 0.80 (d, J = 6.4 Hz, 6 H); I3C NMR in DzO (6) d: 14.8, H ) , 4 . 1 1 ( q , J = 7 . 1 H z , 2 H ) , 3 . 4 5 ( d d , J = 4 . 1 , 4 . 2 H z , 1H),3.31 15.7, 17.5, 28.4, 35.5, 37.6,41.2,44.3,47.3, 67.4; u: 27.1, 30.2, 31.4, (dd, J = 5.6, 5.7 Hz, 1 H), 2.67 (m, 1 H), 2.47-2.31 (m, 3 H), 2.1953.2,61.4,64.9; IR (cm-I) 3664,2958,2932,2754, 1464, 1380, 1312, 1.81 (m, 5 H), 1.73-1.42 (m, 5 H), 1.38-0.85 (m, 3 H), 1.23 (t, J = 1268, 1010; MS ( d z , %) 251 (M', 7), 250 (34), 236 (4), 234 (5), 222 7.1 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 0.79 (d, J = 5.8 Hz,3 H). (6), 220 (21), 194 (42), 181 (2), 164 (5), 152 (15), 112 (27), 111 (100); Lithium bis(trimethylsily1)amide (0.36 mL, 0.36 mmol, 1.0 M in HRMS cald for Cl6HzsNO 25 1.2260, found: 25 1.2257. This material THF) was added to a solution of the benzenesulfonylated 16 (101.0 was found to be identical to the natural alkaloid by 'H NMR, I3CNMR, mg, 0.18 mmol) in THF (2 mL) at -78 "C. After 2 h with warming GC-MS (coinjection on a capillary gc column), and GC-lT/IR. to room temperature, the reaction mixture was quenched with brine (2 mL) and diluted ether (2 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3 x 4 mL). The combined Acknowledgment. We thank M. P. Doyle and T. F. S p a d e organic extract was dried (KzCOs), concentrated, and chromatographed for helpful discussions, and Zeneca Pharmaceuticals for financial to give 17 (55.7 mg, 53% yield from 16)as a light brown oil: TLC Rf support. 0.67 (20% ethyl acetate/petroleum ether); 'H NMR (6) 7.31 (m, 5 H), 4 . 5 2 ( ~ , 2 H ) , 4 . 1 5 ( q , J = 7 . 1 H z , 2 H ) , 3 . 5 4 ( d d , J = 4 . 9 , 4 . 2 H z ,1 JA9437666
